AGM STUDIES: A crucial element in understanding the pathogenesis of lentiviral infections is to compare and contrast parameters between progressive and non-progressive infections. Indeed, elucidating the mechanisms underlying AIDS resistance of SIV-infected natural hosts may provide crucial information to better understand AIDS pathogenesis. To date, >40 primate lentiviruses have been found to naturally infect African nonhuman primate hosts at high prevalence levels. In general, SIVs infecting African species evolved through host-dependent evolution, meaning that they have infected different NHP species for thousands, or hundreds of thousands, of years, possibly since primate speciation. During this long history, SIVs and their natural hosts evolved to coexistence, with the African NHPs infected with their species-specific viruses generally not showing signs of SIV-induced disease or simian AIDS. To determine mechanisms by which natural host African nonhuman primates are able to survive SIV infection without progression to chronic infection we have studied the phenotypes, frequencies, functionality, and SIV-infection frequency within individual T cell subsets of SIVagm-infected and uninfected African green monkeys. We believe these studies will lead to an understanding of how these animals are able to live with SIVagm and not progress through chronic infection and avoid simian AIDS. We have found that (1) Most CD4 T cells from African green monkeys down-regulate CD4 in vivo as they enter the memory pool, (2) Down regulation of CD4 by memory T cells is independent of SIV infection, (3) the CD4 negative memory T cells maintain functions which are normally attributed to CD4 T cells including production of IL-2, production of IL-17, expression of FoxP3 and expression of CD40L (4) loss of CD4 expression protects these T cells from infection by SIV in vivo and (5) these CD4 negative T cells maintain MHC-II restriction. Hence downregulation of CD4 as CD4 T cells enter the memory pool, with maintenance of CD4 T cell effector functions, is a likely mechanism by which AGM are able to live with SIVagm and avoid disease progression. We have also initiated studies to understand the molecular mechanism by which CD4 protein is down regulated as AGM nave CD4 T cells are stimulated to enter the memory pool. In collaboration with Dr. Remy Bosselut, we have begun investigating the expression pattern and genetic sequence of several transcription factors known to be critically important for CD4 and CD8 lineage selection. MICROBIAL TRANSLOCATION STUDIES Progressive lentiviral infection of primates is associated with a multifaceted activation of the immune system. This chronic immune activation has been shown to be tightly associated with HIV and SIV disease progression. We recently showed that one of the major causes of this chronic immune activation was microbial translocation. During the acute phase of infection the structural and immunological barrier of the gastrointestinal tract are damaged and microbial products consequently translocate from the lumen into peripheral circulation. In circulation these microbial products can stimulate the adaptive and innate arms of the immune system. Indeed, we found significant correlations between microbial translocation and measures of immune activation in chronically HIV/SIV-infected individuals. To determine the role of microbial translocation in immune activation and disease progression, and to investigate potential modulation of microbial translocation induced immune activation we plan to use a non-human primate model of HIV infection. It is well known that SIV-infected pigtail macaques (PTM) are infected with SIV and the animals rapidly progress into chronic infection. Moreover, SIV-infected PTM are characteristically plagued by significant gastrointestinal pathology. Hence, we believe these animals have more microbial translocation than either HIV-infected humans or SIV-infected rhesus macaques. We are studying microbial translocation, the underlying mechanisms, and its role in immune activation and disease progression in SIV-infected PTM. We have seen that PTM have significantly higher levels of microbial translocation prior to infection than rhesus macaques, AGM, sooty mangabeys, or humans. Moreover, these animals have higher increases in microbial translocation than any other primate species we have studied. Therefore the rapid progressive phenotype associated with PTM is partially attributed to microbial translocation-induced immune activation. We are furthering these studies by performing therapeutic interventions in SIV-infected PTM with compounds known to decrease microbial translocation.